Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. The single nucleotide polymorphism rs, causing a substitution of valine Val to leucine Leu in the adenylyl cyclase 2 ADCY2has previously been associated with bipolar disorder BD. Mice homozygous for the Leu variant display symptoms of a mania-like state accompanied by cognitive impairments. Mutant animals show additional characteristic signs of rodent mania models, i. Exposure to chronic social defeat stress switches homozygous Leu variant carriers from a mania- to a depressive-like state, a transition which is reminiscent of the alternations characterizing the symptomatology in BD patients. Single-cell RNA-seq scRNA-seq revealed widespread Adcy2 mRNA expression in numerous hippocampal cell types. Differentially expressed genes particularly identified from glutamatergic CA1 neurons point towards ADCY2 variant-dependent alterations in multiple biological processes including cAMP-related signaling pathways. These results validate ADCY2 as dating someone with manic depression BD risk gene, provide insights into underlying disease mechanisms, and potentially open novel avenues for therapeutic intervention strategies. Bipolar disorder BD collectively terms a group of chronic psychiatric disorders characterized by recurrent manic and depressive episodes. This group of mental disorders is accompanied by severely impaired psychosocial functioning and premature mortality [ 2 ]. Genome-wide association studies GWAS have identified numerous loci associated with BD over the past years [ 678910111213 ]. Among these loci, the adenylyl cyclase 2 gene ADCY2 has been identified as a potential risk gene for BD [ 14 ], a finding which has been replicated by the latest, and to date largest, BD GWAS meta-analyses [ 1516 ]. Their activity is controlled dating someone with manic depression heteromeric G proteins. Thereby, these enzymes are capable of integrating signals from various G protein-coupled receptors GPCRs which are conveyed onto downstream signaling pathways via the second messenger cAMP [ 17 ]. The family of mammalian membrane-bound ADCYs comprises 9 isoforms, which are classified according to their signaling properties. Similar to all other ADCYs, ADCY2 is expressed in the central nervous system but displays a distinct and broader expression pattern compared to other group II ADCYs [ 18 ]. In the past decades, psychiatric research has particularly focused on neurotransmitter- and neuromodulator-related GPCRs as potential risk factors and drug targets for therapeutic intervention [ 1920 ]. In contrast, ADCYs, which are essential for the generation of the second messenger cAMP, have largely been ignored [ 21 ]. This is somewhat surprising as accumulating evidence from human [ 14222324 ] and mouse [ 252627282930 ] studies suggests an involvement of different ADCYs in psychiatric disorders including autism, schizophrenia, depression and BD. In contrast to the vast majority of disease-associated SNPs, which are intergenic or intronic, one of the BD-associated SNPs - rs - is located in the 3 rd exon of the ADCY2 gene Fig. Hence, it encodes a missense mutation resulting in a Val to Leu substitution at position ValLeu within the 4 th transmembrane helix of the first transmembrane domain Fig. Among ADCYs, this missense mutation is unique and its functional consequences are unclear. In ADCY2 homologs of different species, Val is fully conserved. Among other family members, however, it is only found in its closest relative ADCY7 Fig. Each dot represents an individual cell. Here we investigated the direct consequences of rs on ADCY2 function in vitro and in vivo. To validate ADCY2 as a potential BD risk gene, we used heterologous expression to study protein function and generated a transgenic mouse model carrying the Val to Leu substitution. The latter approach allowed us to interrogate effects of the missense mutation with regards to BD-related endophenotypes and to probe its potential interaction with chronic stress as an environmental risk factor. Finally, we unraveled how the presence of the disease-associated SNP altered the transcriptional landscape in the ventral hippocampus, a brain structure involved in the regulation of emotionality and BD-related behavioral phenotypes. Expression vectors pcDNA3. Protein expression was assessed by Western blot and immunofluorescence. For details, refer to online Supplementary Information. Cell lines, originally purchased from the American Type Culture Collection, are regularly tested for mycoplasma contamination using PCR test. All dating someone with manic depression experiments were conducted with the approval of and in accordance with the Guide of the Care and Use of Laboratory Animals of the Government of Upper Bavaria, Germany Az. All experiments were conducted with adult male mice age: 2—5 months. The ssODN contained 2 silent mutations, one that added a restriction enzyme site Alu I for genotyping purposes and another one that obliterated the PAM sequence NGG so that the donor DNA was not cleaved by Cas9 Fig.
Cell Signal. The ssODN contained 2 silent mutations, one that added a restriction enzyme site Alu I for genotyping purposes and another one that obliterated the PAM sequence NGG so that the donor DNA was not cleaved by Cas9 Fig. Besides genetic associations of ADCYs [ 14 , 22 , 24 , 26 ], general alterations in cAMP-dependent signaling pathways have been linked to psychiatric disorders [ 21 , 57 , 58 ]. Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned. Article PubMed CAS Google Scholar Palmer GC. Signaling networks in the pathophysiology and treatment of mood disorders.
Materials and methods
Bipolar affective disorder is a serious mood disorder characterized by manic and depressive mood swings. Objective: Research in adults has identified an association between bipolar disorder and suicidal behavior. It is argued that among studies that were published within recent decades to this. This relationship, however. Compares development within the fields of medical genetics and psychiatry. Exposure to chronic social defeat stress switches homozygous Leu variant carriers from a mania- to a depressive-like state, a transition which.J Biol Chem. Specialized prior knowledge is not required. Shahoha M, Cohen R, Ben-Simon Y, Ashery U. Griebel G, Holsboer F. Article PubMed PubMed Central CAS Google Scholar Chen X, Luo J, Leng Y, Yang Y, Zweifel LS, Palmiter RD, et al. Article PubMed CAS Google Scholar Wray NR, Pergadia ML, Blackwood DH, Penninx BW, Gordon SD, Nyholt DR, et al. Article PubMed CAS Google Scholar Risby ED, Hsiao JK, Manji HK, Bitran J, Moses F, Zhou DF, et al. Revised : 21 June Protein expression was assessed by Western blot and immunofluorescence. The genetics of bipolar disorder. Proc Natl Acad Sci USA. Search Search articles by subject, keyword or author. Wang H, Xu J, Lazarovici P, Quirion R, Zheng W. Inhibitors of membranous adenylyl cyclases. Their behavioral response, however, differed significantly. Differentially expressed genes particularly identified from glutamatergic CA1 neurons point towards ADCY2 variant-dependent alterations in multiple biological processes including cAMP-related signaling pathways. Our results suggest that the impaired activity is not a consequence of reduced enzyme levels but is rather related to altered subcellular localization induced by the Val to Leu substitution in the 4 th transmembrane helix of transmembrane domain M1. In view of the reduced performance in the MWM, we additionally evaluated hippocampal long-term potentiation LTP at CA3-CA1 synapses. Directions Patient Admission Patient Discharge Stay » Zur Übersicht Food Supply for Patients Lost and Found. Patch-clamp experiments were used for recording miniature excitatory postsynaptic currents mEPSCs and miniature inhibitory postsynaptic currents mIPSCs in the ventral hippocampus. Article PubMed PubMed Central CAS Google Scholar Razzoli M, Andreoli M, Maraia G, Di Francesco C, Arban R. Article PubMed CAS Google Scholar Wozny C, Maier N, Fidzinski P, Breustedt J, Behr J, Schmitz D. Please click on this confirmation link to activate your registration. Next, we aimed at investigating the in vivo consequences of rs on mouse behavior. Mice homozygous for the Leu variant display symptoms of a mania-like state accompanied by cognitive impairments. Excitatory and inhibitory synaptic dysfunction in mania: an emerging hypothesis from animal model studies. Article PubMed CAS Google Scholar Moreno-Mateos MA, Vejnar CE, Beaudoin JD, Fernandez JP, Mis EK, Khokha MK, et al. Perry W, Minassian A, Henry B, Kincaid M, Young JW, Geyer MA. JavaScript scheint in Ihrem Browser deaktiviert zu sein. Its causes are manifold and for the most part still not understood. First name. The gene ontology enrichment analysis of DEGs using the KEGG database yielded the highest number of affected processes and pathways in glutamatergic CA1 neurons. This group of mental disorders is accompanied by severely impaired psychosocial functioning and premature mortality [ 2 ]. German Center for Neurodegenerative Diseases DZNE site Munich, , Munich, Germany.
